Cachexia is a serious medical condition in many chronic diseases, such as cancer, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), chronic kidney disease (CKD) and some infectious diseases, affecting about 6 million people in the U.S. annually. It is characterized by loss of muscle mass (catabolic wasting) and often leads to reduced exercise capacity (exercise intolerance) and mortality. Skeletal muscle abnormalities caused by excess production of reactive oxygen species (ROS) and the consequent cellular damages underlie these detrimental conditions. It is well known that oxidative muscles are resistant to catabolic wasting; however, the underlying mechanisms remain elusive. We have shown recently in a mouse model of CHF [cardiac-specific calsequestrin (CSQ) transgenic mice] that this oxidative phenotype-associated protection in skeletal muscle is due to a nitric oxide (NO)-dependent antioxidant defense possibly through activation of the Keap1/Nrf2 scaffold protein-transcription factor complex, whereas fast-twitch glycolytic muscles lack such a protective mechanism and are vulnerable to cachectic stimuli. Our preliminary data shows that extracellular superoxide dismutase (EcSOD or SOD3) is highly expressed in oxidative and exercise- trained muscles, and augmenting NO enhances SOD3 expression and reduces catabolic wasting in glycolytic muscles. These findings indicate the functional importance of this NO-SOD3-dependent defense in skeletal muscle, which may underlie not only the protection associated with the oxidative phenotype, but also the salutary impact of endurance exercise training. We hypothesize that NO protects skeletal muscle from catabolic wasting through activation of the Keap1/Nrf2 protein complex and induction of SOD3 expression. To test this hypothesis, we propose: 1) To ascertain the functional role of SOD3 in skeletal muscle against catabolic wasting and exercise intolerance in CHF; and 2) To elucidate the molecular switch in the NO-dependent antioxidant defense. If our hypothesis proves to be correct, we will have uncovered a novel and important cellular defense mechanism in skeletal muscle. The studies may provide new information for more effective therapeutics for muscle wasting and exercise intolerance associated with numerous chronic diseases.